Project Summary Based on genetic and cellular discoveries made in the PI's lab, this proposal focuses on novel mechanisms that are critical for formation of heart valves. Preliminary data presented in the proposal show that mutations in the DCHS1 gene cause a very common heart valve disease (i.e., mitral valve prolapse) and can be caused by errors in how valve tissue forms during development. As such, molecular, cellular, and bioengineering approaches will be utilized to test specific hypotheses on how DCHS1 functions during valve development. Extensive collaborations with the COBRE core facilities (Bioengineering and Bioimaging Core and Cell, Tissue, and Molecular Analysis Core) will provide unique opportunities to answer biophysical questions about heart- valve diseases that heretofore have been impossible to answer using even state-of-the-art biological and genetic approaches. Understanding the developmental pathogenetic mechanisms that contribute to valve disease will allow us, during the course of the COBRE, to integrate with other target faculty (Dr. Jeoung Soo Lee [project: therapeutic nanoparticle delivery], Dr. A. Simionescu [project: stem cells and acellular scaffolds]) to evolve the PI's studies towards regeneration of diseased valve tissue. Additionally, scientific (Dr. Roger Markwald) and clinical (Dr. John Ikonimidis) mentors will serve to accelerate the PI's discoveries through regularly scheduled meetings and facilitate interactions with core facilities and target faculty in this COBRE. Mitral valve prolapse (MVP) affects 1 in 40 individuals worldwide. Defined as billowing of the mitral leaflets into the left atrium, it is the most common cause of isolated mitral regurgitation requiring surgical repair. Its complications include congestive heart failure, endocarditis, atrial arrhythmias, and sudden death. The proposed work capitalizes on previously unrecognized genetic data collected from MVP patients; studies in the mouse show that this class of genes is an important and previously unrecognized contributor to valve structural development, valve biomechanical properties and disease pathogenesis. The uncovering of this particular disease gene and the processes it regulates holds great potential for future remedial or therapeutic insight towards regeneration or formation of mechanically stable valve tissue that will be beneficial to MVP patients.